CoChat
Sign Up
Cited by 193Tissue Engineering and Regenerative MedicineCollagen: Extraction and CharacterizationHydrogels: synthesis, properties, applications

Crosslinking strategies for preparation of extracellular matrix-derived cardiovascular scaffolds

Open access
Ma, B., Wang, X., Wu, C., Chang, J.·2014·Regenerative Biomaterials
DOI 10.1093/rb/rbu009PMC PMC4669006
Open this paper in CoChat — free accountOpen PDF

Abstract

Heart valve and blood vessel replacement using artificial prostheses is an effective strategy for the treatment of cardiovascular disease at terminal stage. Natural extracellular matrix (ECM)-derived materials (decellularized allogeneic or xenogenic tissues) have received extensive attention as the cardiovascular scaffold. However, the bioprosthetic grafts usually far less durable and undergo calcification and progressive structural deterioration. Glutaraldehyde (GA) is a commonly used crosslinking agent for improving biocompatibility and durability of the natural scaffold materials. However, the nature ECM and GA-crosslinked materials may result in calcification and eventually lead to the transplant failure. Therefore, studies have been conducted to explore new crosslinking agents. In this review, we mainly focused on research progress of ECM-derived cardiovascular scaffolds and their crosslinking strategies.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1093/rb/rbu009

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Cross-linking agents have been successfully employed to enhance enzymatic resistance, matrix decomposition, and ultimately improve biomechanical strength in various tissues and organs.

    “Cross-linking agents have been successfully employed to enhance enzymatic resistance, matrix decomposition, and ultimately improve biomechanical strength in various tissues and organs [[171], [172], [173]].”

    From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [172]

    The Introduction and Conclusions and Future Perspective sections say crosslinking prevents degeneration and enhances the mechanical strength of ECM-derived cardiovascular scaffolds. The Chemical crosslinking agents section also reports resistance to enzymatic degradation for EDC-crosslinked collagen. The claim's assertion that crosslinking enhances matrix decomposition reverses the paper's point, and its reference to various tissues and organs is broader than the cardiovascular scaffolds discussed. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Crosslinkers effectively improve the mechanical properties of ECM.

    “Whereas they effectively improve the mechanical properties of ECM [60,192,193]”

    From Immune Response to Extracellular Matrix Bioscaffolds: A Comprehensive Review (2025) · cites this paper as [193]

  • Genipin's clinical applicability is limited due to the dark blue appearance of scaffold after treatment by genipin, high cost, and the complex extraction process.

    “However, despite its biocompatibility and effectiveness, genipin's clinical applicability is limited due to the dark blue appearance of scaffold after treatment by genipin, high cost, and the complex extraction process [172].”

    From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [172]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 73

  1. [1]Rahimtoola SH Choice of prosthetic heart valve for adult patients. J Am Coll Cardiol 2003; 41: 893– 904. 12651032
  2. [2]Julie RF Boris AN Joseph PV Tissue engineering: a 21st century solution to surgical reconstruction. Ann Thorac Surg 2001; 72: 577– 91. 11515900
  3. [3]Cannegieter SC Rosendaal FR Briet E Thrombembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 1994; 89: 635– 41. 8313552
  4. [4]Ralf S Simon PH Jason SS Tissue engineering of heart valves: in vitro experiences. Ann Thorac Surg 2000; 70: 140– 4. 10921698
  5. [5]Kirklin JK Smith D Novick W Long-term function of cryopreserved aortic homografts. J Thorac Cardiovasc Surg 1993; 106: 154– 66. 8320994
  6. [6]Mitchell RN Jonas RA Schoen FJ Pathology of explanted cryopreserved allograft heart valves: comparison with aortic valves from orthotopic heart transplants. J Thorac Cardiovasc Surg 1998; 115: 118– 27. 9451054
  7. [7]Simon P Kasimir MT Seebacher G Early failure of the tissue engineered porcine heart valve SYNERGRAFT in pediatric patients. Eur J Cardiothorac Surg 2003; 23: 1002– 6. 12829079
  8. [8]Karen M Frederick JS Heart valve tissue engineering concepts, approaches, progress, and challenges. Ann Biomed Eng 2006; 34: 1799– 819. 17053986 PMC1705506
  9. [9]Roberto JM Joshua MU Shawn MG Tissue-engineered vascular grafts: autologous off-the-shelf vascular access? Semin Nephrol 2012; 32: 582– 91. 23217339
  10. [10]Avione YL Nathan M Cameron B Regenerative implants for cardiovascular tissue engineering. Transl Res 2014; 163: 3221– 41. 24589506
  11. [11]Thomas LV Lekshmi V Nair PD Tissue engineered vascular grafts—preclinical aspects. Int J Cardiol 2013; 167: 1091– 100. 23040078
  12. [12]Swathi R Elliot LC Biomaterials for vascular tissue engineering. Regen Med 2010; 5: 107. 20017698 PMC2822541
  13. [13]Schoen FJ Levy RJ Calcification of tissue heart valve substitutes: progress toward understanding and prevention. Ann Thorac Surg 2005; 79: 1072– 80. 15734452
  14. [14]Dahl SL Koh J Prabhakar V Decellularized native and engineered arterial scaffolds for transplantation. Cell Transplant 2003; 12: 659– 66. 14579934
  15. [15]Schmidt CE Baier JM Acellular vascular tissues: natural biomaterials for tissue repair and tissue engineering. Biomaterials 2000; 21: 2215– 31. 11026628
  16. [16]Courtman DW Errett BF Wilson GJ The role of crosslinking in modification of the immune response elicited against xenogenic vascular acellular matrices. J Biomed Mater Res 2001; 55: 576– 86. 11288086
  17. [17]Sung HW Hsu CS Lee YS Physical properties of a porcine internal thoracic artery fixed with an epoxy compound. Biomaterials 1996; 17: 2357– 65. 8982476
  18. [18]Sung HW Hsu HL Shih CC Cross-linking characteristics of biological tissues fixed with monofunctional or multifunctional epoxy compounds. Biomaterials 1996; 17: 1405– 10. 8830967
  19. [19]Jorge-Herrero E Fernández P Turnay J Influence of different chemical cross-linking treatments on the properties of bovine pericardium and collagen. Biomaterials 1999; 20: 539– 45. 10213357
  20. [20]Cao H Xu SY EDC/NHS-crosslinked type II collagen-chondroitin sulfate scaffold: characterization and in vitro evaluation. J Mater Sci Mater Med 2008; 19: 567– 75. 18058201
  21. [21]Olde Damink LH Dijkstra PJ van Luyn MJ In vitro degradation of dermal sheep collagen cross-linked using a water-soluble carbodiimide. Biomaterials 1996; 17: 679– 84. 8672629
  22. [22]Norbert WG Inka J Hanngörg Z Detoxification and endothelialization of glutaraldehyde-fixed bovine pericardium with titanium coating a new technology for cardiovascular tissue engineering. Circulation 2009; 119: 1653– 60. 19289635
  23. [23]Jayakrishnan A Jameela SR Glutaraldehyde as a fixative in bioprostheses and drug delivery matrices. Biomaterials 1996; 17: 471– 84. 8991478
  24. [24]Sang SK Sang HL Seung WC Tissue engineering of heart valves by recellularization of glutaraldehyde-fixed porcine valves using bone marrow-derived cells. Exp Mol Med 2006; 38: 273– 83. 16819286
  25. [25]Chen W Schoen FJ Levy RJ Mechanism of efficacy of 2-amino oleic acid for inhibition of calcification of glutaraldehyde-pretreated porcine bioprosthetic heart valves. Circulation 1994; 90: 323– 9. 8026014
  26. [26]Jorge-Herrero E Ferna´ndez P Escudero C Calcification of pericardial tissue pretreated with different amino acids. Biomaterials 1996; 17: 571– 5. 8652775
  27. [27]Cheul L Soo HK Seung HC High-concentration glutaraldehyde fixation of bovine pericardium in organic solvent and post-fixation glycine treatment: in vitro material assessment and in vivo anticalcification effect. Eur J Cardio Thorac Surg 2011; 39: 381– 7. 20739186
  28. [28]Vyavahare N Hirsch D Lerner E Prevention of bioprosthetic heart valve calcification by ethanol preincubation. Efficacy and mechanisms. Circulation 1997; 95: 479– 88. 9008467
  29. [29]Pathak CP Adams AK Simpson T Treatment of bioprosthetic heart valve tissue with long chain alcohol solution to lower calcification potential. J Biomed Mater Res A 2004; 69: 140– 4. 14999761
  30. [30]Vyavahare NR Ogle M Schoen FJ Elastin calcification and its prevention with aluminum chloride pretreatment. Am J Pathol 1999; 155: 973– 82. 10487855 PMC1866878
  31. [31]Sung HW Chang WH Ma CY Crosslinking of biological tissues using genipin and carbodiimide. J Biomed Mater Res A 2003; 64: 427– 38. 12579556
  32. [32]Olde Damink LH Dijkstra PJ van Luyn MJ Cross-linking of dermal sheep collagen using a water-soluble carbodiimide. Biomaterials 1996; 17: 765– 73. 8730960
  33. [33]Sung HW Chang Y Chiu CT Crosslinking characteristics and mechanical properties of a bovine pericardium fixed with a naturally occurring crosslinking agent. J Biomed Mater Res 1999; 47: 116– 26. 10449623
  34. [34]Van Wachem PB Brouwer LA Zeeman R In vivo behavior of epoxy-crosslinked porcine heart valve cusps and walls. J Biomed Mater Res 2000; 53: 18– 27. 10634948
  35. [35]Chiono V Pulieri E Vozzi G Genipin-crosslinked chitosan/gelatin blends for biomedical applications. J Mater Sci Mater Med 2008; 19: 889– 98. 17665102
  36. [36]Sung HW Liang IL Chen CN Stability of a biological tissue fixed with a naturally occurring crosslinking agent (genipin). J Biomed Mater Res 2001; 55: 538– 46. 11288082
  37. [37]Liang HC Chang WH Lin KJ Genipin-crosslinked gelatin microspheres as a drug carrier for intramuscular administration: in vitro and in vivo studies. J Biomed Mater Res A 2003; 65: 271– 82. 12734822
  38. [38]Chang Y Tsai CC Liang HC In vivo evaluation of cellular and acellular bovine pericardia fixed with a naturally occurring crosslinking agent (genipin). Biomaterials 2002; 23: 2447– 57. 12033592
  39. [39]Sung HW Huang RN Huang LL Feasibility study of a natural crosslinking reagent for biological tissue fixation. J Biomed Mater Res 1998; 42: 560– 7. 9827680
  40. [40]Koob TJ Hernandez DJ Mechanical and thermal properties of novel polymerized NDGA gelatin hydrogels. Biomaterials 2003; 24: 1285– 92. 12527270
  41. [41]Koob TJ Willis TA Hernandez DJ Biocompatibility of NDGA-polymerized collagen fibers. I. Evaluation of cytotoxicity with tendon fibroblasts in vitro. J Biomed Mater Res 2001; 56: 31– 9. 11309788
  42. [42]Fujimoto N Kohta R Kitamura S Estrogenic activity of an antioxidant, nordihydro-guaiaretic acid (NDGA). Life Sci 2004; 74: 1417– 25. 14706572
  43. [43]Ju YM Yu B Koob TJ A novel porous collagen scaffold around an implantable biosensor for improving biocompatibility. I. In vitro/in vivo stability of the scaffold and in vitro sensitivity of the glucose sensor with scaffold. J Biomed Mater Res A 2008; 87: 136– 46. 18085651
  44. [44]Rivero S Garcia MA Pinotti A Crosslinking capacity of tannic acid in plasticized chitosan films. Carbohydr polym 2010; 82: 270– 6.
  45. [45]Santos BC Scalbert A Proanthocyanidins and tannin-like compounds: nature, occurrence, dietary intake and effects on nutrition and health. J Sci Food Agric 2000; 80: 1094– 117.
  46. [47]Barbehenn RV Peter Constabel C Tannins in plant–herbivore interactions. Phytochemistry 2011; 72: 1551– 65. 21354580
  47. [48]Frazier RA Deaville ER Green RJ Interactions of tea tannins and condensed tannins with proteins. J Pharm Biomed Anal 2010; 51: 490– 5. 19553056
  48. [49]Isenburg JC Karamchandani NV Simionescu DT Structural requirements for stabilization of vascular elastin by polyphenolic tannins. Biomaterials 2006; 27: 3645– 51. 16527345
  49. [50]Isenburg JC Simionescu DT Vyavahare NR Tannic acid treatment enhances biostability and reduces calcification of glutaraldehyde fixed aortic wall. Biomaterials 2005; 26: 1237– 45. 15475053
  50. [51]Guyot S Marnet N Sanoner P Variability of the polyphenolic composition of cider apple (Malus domestica) fruits and juices. J Agric Food Chem 2003; 51: 6240– 7. 14518950
  51. [52]Zhai W Chang J Lü X Procyanidins cross linked heart valve matrix: anticalcification effect. J Biomed Mater Res B 2009; 90: 913– 21. 19353570
  52. [53]Schoen FJ Heart valve tissue engineering-quo vadi? Curr Opin Biotechnol 2011; 22: 698– 705. 21315575
  53. [54]Han B Nimni ME Transdermal delivery of amino acids and antioxidants enhance collagen synthesis: in vivo and in vitro studies. Connect Tissue Res 2005; 46: 251– 7. 16546829
  54. [55]Keqin Ou Liwei Gu Absorption and metabolism of proanthocyanidins. J Funct Foods 2014; 7: 43– 53.
  55. [56]Debasis B Chandan KS Sidhartha DR Molecular mechanisms of cardioprotection by a novel grape seed proanthocyanidin extract. Mutat Res 2003; 523–524: 87– 97. 12628506
  56. [57]Strek M Gorlach S Podsedek A Procyanidin oligomers from Japanese quince (Chaenomeles japonica) fruit inhibit activity of MMP-2 and MMP-9 metalloproteinases. J Agric Food Chem 2007; 55: 6447– 52. 17616210
  57. [58]Nomoto H Iigo M Hamada H Chemoprevention of colorectal cancer by grape seed proanthocyanidin is accompanied by a decrease in proliferation and increase in apoptosis. Nutr Cancer 2004; 49: 81– 8. 15456639
  58. [59]Wanyin Z Chunping J Hui Z Procyanidins inhibit tumor angiogenesis by crosslinking extracellular matrix. Chin J Cancer Res 2011; 23: 99– 106. 23483060 PMC3587545
  59. [60]Teissedre PL Frankel EN Waterhouse AL Inhibition of in vitro human LDL oxidation by phenolic antioxidants from grapes and wines. J Sci Food Agric 1996; 70: 55– 61.
  60. [61]Singh RP Tyagi AK Dhanalakshmi S Grape seed extract inhibits advanced human prostate tumor growth and angiogenesis and upregulates insulin-like growth factor binding protein-3. Int J Cancer 2004; 108: 733– 40. 14696100
  61. [62]Zhai W Chang J Lin K Crosslinking of decellularized porcine heart valve matrix by procyanidins. Biomaterials 2006; 27: 3684– 90. 16513164
  62. [63]Han B Jaurequi J Tang WB Proanthocyanidin: a natural crosslinking reagent for stabilizing collagen matrics. J Biomed Mater Res A 2003; 65: 118– 24. 12635161
  63. [64]Hagerman AE Butler LG The specificity of proanthocyanidin–protein interactions. J Biol Chem 1981; 256: 4494– 7. 7217094
  64. [65]Kookmin MK Guillermo AH Harold DB Role of glutaraldehyde in calcification of porcine aortic valve fibroblasts. Am J Pathol 1999; 154: 843– 52. 10079262 PMC1866403
  65. [66]Fartasch M Haneke E Hornstein OP Mineralization of collagen and elastic fibers in superficial dystrophic cutaneous calcification: an ultrastructural study. Dermatologica 1990; 181: 187– 92. 2269376
  66. [67]Gura TA Wright KL Veis A Identification of specific calcium-binding non-collagenous proteins associated with glutaraldehyde-preserved bovine pericardium in the rat subdermal model. J Biomed Mater Res 1997; 35: 483– 95. 9189826
  67. [68]Handford PA Fibrillin-1, a calcium binding protein of extracellular matrix. Biochim Biophys Acta 2000; 1498: 84– 90. 11108952
  68. [69]Paule WJ Bernick S Strates B Calcification of implanted vascular tissues associated with elastin in an experimental animal model. J Biomed Mater Res 1992; 26: 1169– 77. 1429765
  69. [70]Bobryshev YV Lord RS Warren BA Calcified deposit formation in intimal thickenings of the human aorta. Atherosclerosis 1995; 118: 9– 21. 8579636
  70. [71]Jason CI Dan TS Naren RV Elastin stabilization in cardiovascular implants: improved resistance to enzymatic degradation by treatment with tannic acid. Biomaterials 2004; 25: 3293– 302. 14980424
  71. [72]Kim KM Apoptosis and calcification. Scanning Microsc 1995; 9: 1137– 78. 8819895
  72. [73]Rajamannan NM Subramaniam M Rickard D Human aortic valve calcification is associated with an osteoblast phenotype. Circulation 2003; 107: 2181– 4. 12719282 PMC3922288
  73. [74]Rajamannan NM Nealis TB Subramaniam M Calcified rheumatic valve neoangiogenesis is associated with vascular endothelial growth factor expression and osteoblast-like bone formation. Circulation 2005; 111: 3296– 301. 15956138 PMC3951870

Cited by

Sorted by citations

Authors
Ma, B., Wang, X., Wu, C., & Chang, J.
Affiliations
Chinese Academy of Sciences (CN)
Corresponding author
Chang, J.
ORCID
Wu, C.
Venue
Regenerative Biomaterials
Publisher
Oxford University Press (OUP)
Published
2014-11-01
Volume
1
Issue
1
Pages
81-89
ISSN
  • 2056-3418 (ISSN-L)
  • 2056-3426
DOI
10.1093/rb/rbu009
PMC
PMC4669006
OpenAlex
W2171925711
Cited by
193
References
1
Citations by year
2026: 5 · 2025: 21 · 2024: 11 · 2023: 21 · 2022: 21 · 2021: 22 · 2020: 17 · 2019: 24 · 2018: 22 · 2017: 17 · 2016: 10 · 2015: 1
FWCI
1.76
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Regenerative Biomaterials (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Physical Sciences › Materials Science › Biomaterials › Collagen: Extraction and Characterization
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
Keywords
extracellular matrix, crosslinking agents, glutaraldehyde, bioprosthetic heart valves, vascular grafts, calcification

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review